Inhibitors of
sterol and
phospholipid biosynthesis in kinetoplastid parasites such as Trypanosoma cruzi, the causative agent of
Chagas' disease, and different species of Leishmania have potent and selective activity as chemotherapeutic agents in vitro and in vivo. Recent work with the
sterol C14 alpha-demethylase inhibitor
D0870, a bis
triazole derivative, showed that this compound is capable of inducing radical parasitological cure in murine models of both acute and chronic
Chagas' disease. Other inhibitors of this type, such as
SCH 56592, have also shown curative, rather than suppressive, activity against T. cruzi in these models. Leishmania species have different susceptibilities to
sterol biosynthesis inhibitors, both in vitro and in vivo. Leishmania braziliensis promastigotes, naturally resistant to C14 alpha-demethylase inhibitors such as
ketoconazole and
D0870, were susceptible to these drugs when used in combination with the
squalene epoxidase inhibitor
terbinafine. Inhibitors of delta 24(25)
sterol methyl
transferase have been shown to act as potent antiproliferative agents against Trypanosoma cruzi, both in vitro and in vivo. New inhibitors of this type which show enhanced activity and novel mechanisms of action have been synthesized. Recent work has also demonstrated that this type of
enzyme inhibitors can block
sterol biosynthesis and cell proliferation in Pneumocystis carinii, a fungal pathogen which had previously been found resistant to other
sterol biosynthesis inhibitors.
Ajoene, an antiplatelet compound derived from garlic, was shown to have potent antiproliferative activity against epimastigotes and amastigotes of Trypanosoma cruzi in vitro; this activity was associated with a significant alteration of the
phospholipid composition of the cells with no significant effects on the
sterol content. In addition, alkyllsophospholipids such as
ilmofosine,
miltefosine and
edelfosine have been shown to block the proliferation of T. cruzi and Leishmania and alter both the
phospholipid and
sterol composition. These results indicate the potential of
lipid biosynthesis inhibitors as useful therapeutic agents in the treatment of
leishmaniasis and
Chagas' disease.